PDB-8vug: Crystal Structure of human Tryptophan 2,3-dioxygenase in complex ...

ID or keywords:

Entry

Database: PDB / ID: 8vug

Title

Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PPN1 inhibitor

Components

Tryptophan 2,3-dioxygenase

Keywords

OXIDOREDUCTASE/INHIBITOR / Inhibitor / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex

Function / homology

Function and homology information

response to nitroglycerin / L-tryptophan catabolic process to acetyl-CoA / tryptophan 2,3-dioxygenase / L-tryptophan 2,3-dioxygenase activity / L-tryptophan catabolic process to kynurenine / Tryptophan catabolism / amino acid binding / oxygen binding / protein homotetramerization / heme binding ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.05 Å

Authors

Geeraerts, Z. / Yeh, S.

Funding support

United States, 2items

Organization	Grant number	Country
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	GM115773	United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	GM151419	United States

Citation

Journal: J.Med.Chem. / Year: 2024
Title: Structural Insights into Protein-Inhibitor Interactions in Human Tryptophan Dioxygenase.
Authors: Geeraerts, Z. / Ishigami, I. / Lewis-Ballester, A. / Pham, K.N. / Kozlova, A. / Mathieu, C. / Frederick, R. / Yeh, S.R.

History

Deposition	Jan 29, 2024	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Aug 21, 2024	Provider: repository / Type: Initial release
Revision 1.1	Sep 4, 2024	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2	Sep 11, 2024	Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8vug.cif.gz	732.1 KB	Display	PDBx/mmCIF format
PDB format	pdb8vug.ent.gz		Display	PDB format
PDBx/mmJSON format	8vug.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	8vug_validation.pdf.gz	2.8 MB	Display	wwPDB validaton report
Full document	8vug_full_validation.pdf.gz	2.9 MB	Display
Data in XML	8vug_validation.xml.gz	51 KB	Display
Data in CIF	8vug_validation.cif.gz	68.9 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/vu/8vug ftp://data.pdbj.org/pub/pdb/validation_reports/vu/8vug	HTTPS FTP

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Related structure data

Related structure data	7lu7C 8vtqC 8vzvC 8w1hC 8w2kC 9at2C 9b17C 9b1qC C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI

Deposited unit

A: Tryptophan 2,3-dioxygenase

B: Tryptophan 2,3-dioxygenase

C: Tryptophan 2,3-dioxygenase

D: Tryptophan 2,3-dioxygenase

hetero molecules

185 kDa, 4 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software

Unit cell

Length a, b, c (Å)	143.805, 154.925, 88.32
Angle α, β, γ (deg.)	90, 90, 90
Int Tables number	18
Space group name H-M	P2₁2₁2

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	A
2	1	A
3	2	A
4	2	A
5	3	A
6	3	A
7	4	A
8	4	A
9	5	A
10	5	A
11	6	A
12	6	A

NCS domain segments:

Beg auth comp-ID: GLY / Beg label comp-ID: GLY / Auth asym-ID: A / Label asym-ID: A

Dom-ID	Component-ID	Ens-ID	End auth comp-ID	End label comp-ID	Auth seq-ID	Label seq-ID
1	1	1	HIS	HIS	39 - 391	23 - 375
2	1	1	HIS	HIS	39 - 391	23 - 375
3	2	2	LEU	LEU	39 - 389	23 - 373
4	2	2	LEU	LEU	39 - 389	23 - 373
5	3	3	LEU	LEU	39 - 389	23 - 373
6	3	3	LEU	LEU	39 - 389	23 - 373
7	4	4	LEU	LEU	39 - 389	23 - 373
8	4	4	LEU	LEU	39 - 389	23 - 373
9	5	5	LEU	LEU	39 - 389	23 - 373
10	5	5	LEU	LEU	39 - 389	23 - 373
11	6	6	LEU	LEU	39 - 389	23 - 373
12	6	6	LEU	LEU	39 - 389	23 - 373

NCS ensembles :

ID	Details
1	Local NCS retraints between domains: 1 2
2	Local NCS retraints between domains: 3 4
3	Local NCS retraints between domains: 5 6
4	Local NCS retraints between domains: 7 8
5	Local NCS retraints between domains: 9 10
6	Local NCS retraints between domains: 11 12

#1: Protein	Tryptophan 2,3-dioxygenase / TDO / Tryptamin 2 / 3-dioxygenase / Tryptophan oxygenase / TRPO / Tryptophan pyrrolase / Tryptophanase Mass: 45182.535 Da / Num. of mol.: 4 / Fragment: UNP residues 18-389 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TDO2, TDO / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P48775, tryptophan 2,3-dioxygenase
#2: Chemical	ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₃₄H₃₂FeN₄O₄
#3: Chemical	ChemComp-ZIQ / alpha-methyl-L-tryptophan Type: L-peptide linking / Mass: 218.252 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₁₂H₁₄N₂O₂
#4: Chemical	ChemComp-A1AD1 / (5P)-5-(1H-indol-3-yl)-1-[(piperidin-4-yl)methyl]-1H-benzotriazole Mass: 331.414 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂₀H₂₁N₅ / Feature type: SUBJECT OF INVESTIGATION
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 125 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.72 Å³/Da / Density % sol: 54.81 %
Crystal grow	Temperature: 298 K / Method: microbatch Details: 50 mM sodium citrate pH 5.6, 2.0% Tacsimate pH 5.0, 5.0% PEG 3350

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

APS

/ Beamline: 31-ID / Wavelength: 0.97932 Å

Detector

Type: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 9, 2023

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.97932 Å / Relative weight: 1

Reflection

Resolution: 2.05→154.93 Å / Num. obs: 123426 / % possible obs: 99.5 % / Redundancy: 6.7 % / CC_1/2: 0.999 / R_merge(I) obs: 0.043 / R_pim(I) all: 0.027 / R_rim(I) all: 0.051 / Net I/σ(I): 17.1

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Num. unique obs	CC_1/2	R_pim(I) all	R_rim(I) all
11.23-154.93	5.5	0.028	866	0.998	0.018	0.033
2.05-2.09	6.1	1.808	5963	0.404	1.172	2.168

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0425	refinement
autoPROC		data reduction
Aimless		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.05→105.62 Å / Cor.coef. F_o:F_c: 0.968 / Cor.coef. F_o:F_c free: 0.967 / WR_factor R_free: 0.224 / WR_factor R_work: 0.201 / SU B: 13.918 / SU ML: 0.158 / Average fsc free: 0.9354 / Average fsc work: 0.9428 / Cross valid method: FREE R-VALUE / ESU R: 0.171 / ESU R Free: 0.145
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2154	6093	4.939 %
R_work	0.1942	117263	-
all	0.195	-	-
obs	-	123356	99.412 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 79.722 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-2.349 Å²	0 Å²	-0 Å²
2-	-	-1.453 Å²	0 Å²
3-	-	-	3.801 Å²

Refinement step

Cycle: LAST / Resolution: 2.05→105.62 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	11755	0	336	125	12216

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.007	0.012	12416
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	11730
X-RAY DIFFRACTION	r_angle_refined_deg	1.468	1.887	16775
X-RAY DIFFRACTION	r_angle_other_deg	0.509	1.791	26898
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	4.67	5	1382
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	18.426	6.111	108
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.36	10	2279
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	12.965	10	648
X-RAY DIFFRACTION	r_chiral_restr	0.068	0.2	1720
X-RAY DIFFRACTION	r_gen_planes_refined	0.007	0.02	14618
X-RAY DIFFRACTION	r_gen_planes_other	0.004	0.02	3150
X-RAY DIFFRACTION	r_nbd_refined	0.233	0.2	2683
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.182	0.2	10570
X-RAY DIFFRACTION	r_nbtor_refined	0.187	0.2	6152
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.071	0.2	6367
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.14	0.2	299
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.016	0.2	1
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.207	0.2	9
X-RAY DIFFRACTION	r_nbd_other	0.272	0.2	29
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.153	0.2	9
X-RAY DIFFRACTION	r_mcbond_it	4.045	4.814	5555
X-RAY DIFFRACTION	r_mcbond_other	4.033	4.814	5555
X-RAY DIFFRACTION	r_mcangle_it	5.809	8.642	6928
X-RAY DIFFRACTION	r_mcangle_other	5.809	8.642	6929
X-RAY DIFFRACTION	r_scbond_it	4.93	5.273	6861
X-RAY DIFFRACTION	r_scbond_other	4.93	5.273	6862
X-RAY DIFFRACTION	r_scangle_it	7.214	9.494	9847
X-RAY DIFFRACTION	r_scangle_other	7.214	9.495	9848
X-RAY DIFFRACTION	r_lrange_it	10.968	58.83	52018
X-RAY DIFFRACTION	r_lrange_other	10.97	58.793	51989
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.094	0.05	11877
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.114	0.05	11573
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.101	0.05	11483
X-RAY DIFFRACTION	r_ncsr_local_group_4	0.104	0.05	11687
X-RAY DIFFRACTION	r_ncsr_local_group_5	0.099	0.05	11542
X-RAY DIFFRACTION	r_ncsr_local_group_6	0.116	0.05	11445

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	A	X-RAY DIFFRACTION	Local ncs	0.09442	0.05009
1	2	A	X-RAY DIFFRACTION	Local ncs	0.09442	0.05009
2	3	A	X-RAY DIFFRACTION	Local ncs	0.11371	0.05008
2	4	A	X-RAY DIFFRACTION	Local ncs	0.11371	0.05008
3	5	A	X-RAY DIFFRACTION	Local ncs	0.101	0.05008
3	6	A	X-RAY DIFFRACTION	Local ncs	0.101	0.05008
4	7	A	X-RAY DIFFRACTION	Local ncs	0.10443	0.05009
4	8	A	X-RAY DIFFRACTION	Local ncs	0.10443	0.05009
5	9	A	X-RAY DIFFRACTION	Local ncs	0.09937	0.05008
5	10	A	X-RAY DIFFRACTION	Local ncs	0.09937	0.05008
6	11	A	X-RAY DIFFRACTION	Local ncs	0.11595	0.05008
6	12	A	X-RAY DIFFRACTION	Local ncs	0.11595	0.05008

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
2.05-2.103	0.399	448	0.395	8436	0.395	9072	0.7	0.717	97.9277	0.38
2.103-2.161	0.309	408	0.336	8410	0.335	8840	0.905	0.884	99.7511	0.319
2.161-2.223	0.3	411	0.3	8203	0.3	8628	0.922	0.919	99.8377	0.279
2.223-2.292	0.294	401	0.271	7907	0.272	8336	0.929	0.938	99.6641	0.248
2.292-2.367	0.274	399	0.247	7711	0.248	8124	0.938	0.953	99.8277	0.219
2.367-2.45	0.266	393	0.227	7459	0.229	7870	0.955	0.966	99.7713	0.197
2.45-2.542	0.251	377	0.213	7184	0.215	7581	0.958	0.971	99.7362	0.183
2.542-2.646	0.266	362	0.211	6906	0.214	7317	0.959	0.973	99.3303	0.184
2.646-2.764	0.247	339	0.21	6646	0.212	7049	0.961	0.975	99.0921	0.184
2.764-2.899	0.236	360	0.211	6340	0.212	6708	0.967	0.975	99.8807	0.19
2.899-3.055	0.234	354	0.199	6046	0.201	6414	0.966	0.977	99.7817	0.182
3.055-3.24	0.258	309	0.206	5732	0.208	6059	0.956	0.974	99.7029	0.198
3.24-3.464	0.237	272	0.205	5426	0.206	5719	0.966	0.975	99.6328	0.203
3.464-3.741	0.223	267	0.195	5045	0.197	5334	0.971	0.981	99.5876	0.201
3.741-4.098	0.203	226	0.176	4583	0.177	4921	0.977	0.983	97.724	0.189
4.098-4.581	0.165	203	0.147	4290	0.148	4507	0.984	0.987	99.6894	0.169
4.581-5.287	0.163	205	0.147	3758	0.148	3972	0.986	0.987	99.7734	0.173
5.287-6.472	0.227	130	0.203	3237	0.204	3384	0.972	0.979	99.4976	0.233
6.472-9.135	0.166	149	0.17	2471	0.17	2682	0.986	0.984	97.6883	0.215
9.135-105.62	0.184	80	0.184	1473	0.184	1569	0.981	0.973	98.9802	0.266

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°²)	L12 (°²)	L13 (°²)	L22 (°²)	L23 (°²)	L33 (°²)	S11 (Å °)	S12 (Å °)	S13 (Å °)	S21 (Å °)	S22 (Å °)	S23 (Å °)	S31 (Å °)	S32 (Å °)	S33 (Å °)	T11 (Å²)	T12 (Å²)	T13 (Å²)	T22 (Å²)	T23 (Å²)	T33 (Å²)	Origin x (Å)	Origin y (Å)	Origin z (Å)
1	1.4543	-1.1397	-0.5428	3.3993	0.3842	0.5817	0.0084	0.0547	-0.1243	-0.3367	-0.0155	0.3563	-0.0918	-0.2106	0.0072	0.0698	0.0313	-0.0283	0.1487	0.0205	0.0442	-39.6257	37.1674	-1.2376
2	3.0281	-0.4727	-1.7851	0.705	0.3519	1.8173	-0.1589	-0.2364	-0.4161	0.0104	0.0756	-0.2076	0.0402	0.4106	0.0833	0.068	-0.0183	-0.0003	0.1295	-0.0092	0.2366	-5.5978	16.9423	-10.4485
3	1.4367	0.0605	0.2442	2.9932	1.7726	2.3129	-0.0068	0.5266	-0.0365	-0.5408	-0.3789	1.0099	-0.0712	-0.5727	0.3857	0.2486	0.04	-0.1988	0.4764	-0.0702	0.3831	-28.8472	32.8647	-28.4992
4	1.7286	-0.1167	-0.4635	1.2444	0.3243	2.9036	-0.0644	-0.4106	0.1176	0.1445	0.0427	-0.272	0.1893	0.4504	0.0217	0.0255	0.03	-0.0283	0.2549	-0.0192	0.0694	-7.2536	42.9006	4.1652

Refinement TLS group

Selection: ALL

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